Pharmacology of Thyroid Hormone Flashcards
Colloid contains
thyroglobulin
Synthesis and release of thyroid hormone
- Uptake of iodide ion by the gland
- Oxidation of iodide ion and the iodination of tyrosyl groups
- Condensation of iodotyrosyl residues to iodothyronyl residues in thyroglobulin
- Proteolysis of thyroglobulin and release of thyroxine and triiodothyronine into blood
- The conversion of thyroxine to triiodothyronine in peripheral tissues
Iodide uptake from the circulation occurs by
sodium-iodide symporter located in the basolatedral plasma membrane of thyroid follicle cell
Sodium-iodide symporter is inhibited by
complex anions such as perchlorate, thiocyanate, pertechnetate
Iodide is extruded from the thyroid follicle cell by
the protein pendrin (sodium-indepedent chloride/iodide transporter) located in the apical membrane
Pendred’s syndrome
the hereditary syndrome of goiter and deafness due to a deficiency or absence of pendrin
Oxidation of iodide to iodine is catalyzed by
the thyroid peroxidase enzyme complex in the presence of hydrogen peroxide
Secretion of thyroid hormone
- Endocytosis of colloid
- Proteolysis
- Release of hormones
80% of T3 is produced by
metabolism of T4 in peripheral tissues by types I, II and III 5’ deiodinases
Type I deiodinase catalyzes
the formation of circulating T3 used by peripheral tissues; requires selenium to function
Type II deiodinase is present/catalyzes
present in brain, hypothalamus, pituitary, placenta and brown adipose tissues; catalyzes the formation of intracellular T3
Type III deiodinase inactivates
inactives both T4 and T3 with preference for T3; metabolizes T4 to inactive rT3; high expressed in CNS, skin, fetal brain, and liver
Conditions and factors that inhibit 5’ deiodinase activity
- Acute and chronic illness
- Caloric deprivation
- Malnutrition
- Glucocorticoids
- beta-adrenergic blocking drugs
- Oral cholecystographic agents
- Amiodarone/PTU
- Fatty acids
Agents that increase metabolism of T4 and T3
- Rifampin
- Phenobarbital
- Carbamazepin
- Phenytoin
- Rifabutin
Major carrier of thyroid hormones
thyroxine binding globulin
Transthyretin
Tyroxine binding pre-albumin (TBPA)
Factors that increase the binding of thyroxine to thyroxin-binding globulin
estrogens, methadone, clofibrate, 5-fluorouracil, heroin, tamoxifen, liver disease, porphyria, HIV
Factors that decrease the binding of thyroxine to thyroxin-binding globulin
glucocorticoids, androgens, L-asparaginase, salicylates, mefenamic acid, fenclofenac, antiseizure medications, furosemide, acute and chronic illness
Allan-Herndon-Dudley syndrome
mutations in the transmembrane transporters of thyroid hormones that leads to an X-linked inherited syndrome of mental retardation and myopathy with low serum T4 levels
Symptoms of hypothyroidism
- Sluggish (progressive weakness)
- Low metabolic rate in many organs
- Complain about feeling cold
- Puffy face, doughy skin
- Hypercholesterolemia
- Decreased HR, SV, CO, and pulse pressure
Thyroid hormone deficiency before birth may lead to
cretinism (dwarfism with mental retardation)
Endemic cretinism
due to extreme deficiency of iodine; goiter may or not be present; high incidence of nerve deafness
Sporadic cretinism
due to failure of thyroid gland to develop normally; due to defect in synthesis of thyroid hormone; goiter present if defect in synthesis is the cause
Simple goiter
TSH levels are very high due to deficient secretion of thyroid hormone; may be due to iodine deficiency; may also be caused by a goitrogen
Hashimoto’s disease
chronic autoimmune thyroiditis; autoantibodies produced against thyroid peroxidase and less often thyroglobuline; thyroxine levels are low; TSH ishigh
Diffuse toxic goiter
thyroid enlargement with hyperthyroidism (Graves’ disease)
Nodular goiter
thyroid enlargment with nodules;
non-toxic: without thyroid hormone production
toxic: with thyroid hormone production (Plummer’s disease)
Thyroid preparations
- Levothyroxine Sodium (Synthroid, Levothyroid, L-T4)
- Liothyronine Sodium (Cytomel, Triostat)
- Liotrix (Euthyroid, Thyrolar)
Levothyroxine sodium (Synthroid, Levothyroid, L-T4, Levoxyl, Tirosint)
Sodium salt of synthetic thyroxine available in tablets and for injection
Liothyronine sodium
Sodium salt of triiodothyronine (T3) available in tablets or injection
Liotrix (Euthyroid, Thyrolar)
Mixture of sodium salts of : Levothyroxine and Liothyronine
When would Liothyronine sodium (T3) be administered instead of Levothyroxine sodium?
if faster action of replacement therapy is desired: recent hypothyroidism, overtreatment with antithyroid drugs, after treatment with radioiodine, after thyroidectomy
What do thyroid hormones do to the heart?
increase cardiac contractility; important to treat patients with initial low doses of levothyroxine (synthroid) until an acceptable dose is reached
Myxedema usually caused by
degeneration and atrophy of thyroid gland
When is a goiter associated with myxedema?
during severe defect in thyroid hormone synthesis and during chronic thyroiditis
Myxedema is often associated with
coronary artery disease
Myxedema coma
end-state of untreated hypothyroidism characterized by weakness, stupor, hypothermia, hypoventilation, hypoglycemia, shock and death
Treatment of myxdema coma
initial large IV dose of levothyroxine to occupy that large pools of free and unoccupied thyroid hormone binding sites
Subclinical hypothyroidism
an elevated TSH level in the face of normal thyroid hormone levels
Symptoms of hyperthyroidism (thyrotoxicosis)
hot, thin, nervous, SOB, flushed skin, increased appetite, muscle weakness, tremor
Diseases with hyperthyroidism
Graves’ disease and Plummer’s disease
Graves’ disease
autoimmune disease; lymphocytes produce a TSH receptor stimulating antibody (TSI); activates thyroid gland by binding to TSH receptors and stimulating thyroid hormone production in a manner identical to that of TSH
Plummer’s disease
may be associated with nodular tumors
Treatment of Graves’ disease
antithyroid drugs and radioiodine (to destroy the gland)
Categories of major antithyroid drugs
- drugs that interfere directly with thyroid hormone synthesis
- Ionic inhibitors: block iodide transport
- Iodide itself: suppresses thyroid hormone synthesis and secretion at high concentrations
- Iodinated contrast media: suppresses T4 to T3 converstion
- Radioactive iodide: destroys gland with ionizing radiations
- Lithium: suppresses synthesis and release of thyroid hormones
Drugs that interfere with thyroid hormone synthesis
- Thioamides
- Aniline derivatives
- Polyhydric phenols
Thioamides
PTU, Methimazole, Carbimazole
Aniline Derivatives
Sulfathiazole, Sulfadiazine
Polyhydric phenols
Resorcinol
MOA of Thioamides
Inhibit thyroid peroxidase enzyme: interfere with the oxidation of iodide ion to iodine, interfere with the incorporation of iodine in tyrosyl groups of thyroglobulin, interfere with coupling of iodotyrosyl groups of thyroglobulin
Difference between PTU and methimazole
PTU inhibits peripheral conversion of T4 to T3; methimazole does not have peripheral effects like PTU
Preferred antithyroid agent during pregnancy
PTU because it crosses the placenta to a lesser extent that methiazole and it has lesser excretion in breast milk
Toxicity of thioamides
nausea, GI distress, rash, fever, agranulocytosis
Anionic inhibitors interfere with
the ability of the thyroid gland to concentrate iodidie ion; rarely used in clinical practice
Anionic inhibitors
Thiocyanate (SCN-)
Perchlorate (ClO-4)
Nitrate (NO-3)
Fluoborate (BF-4)
Iodide is used to
prepare patients of Graves’ disease for thyroidectomy (to reduce vascularity of the gland)
Clinical effects of iodide on thyroid gland
Vascularity is reduced; gland becomes firm and hard to touch; follicular cells become smaller; colloid reaccumulates in follicles; quantity of bound iodine increases
Most important MOA of iodide
inhibits the release of thyroid hormone
Caution with the clinical use of iodide
iodide accumulates in the thyroid gland and may render later treatments with thioamides and radioactive iodine ineffective
Iodinated contrast media
ipodate, diatrizoate, iohexol
What can happen to patients being treated for psychiatric diseases with lithium salts
can develop hypothyroidism with a goiter due to the inhibitory effect of lithium on organification of iodide, suppression of coupling of iodothyrosine residues and the release of thyroid hormones
